Erythropoietin, known for its role in erythroid differentiation, is required for normal blood as well as heart and brain development. Erythropoietin stimulates progenitor cells from multiple origins: hematopoietic, endothelial, muscle and neural. We have previously shown that erythropoietin can stimulate muscle satellite cells to proliferate and inhibit differentiation and fusion into myotubes. Although high levels of erythropoietin receptor are expressed in embryonic brain, the role for erythropoietin during brain development is uncertain. We found that erythropoietin is neural protective and acts to stimulate neural progenitor cells and prevent apoptosis in the embryonic brain. Mice lacking the erythropoietin receptor exhibit severe anemia and die around embryonic day 13.5. By embryonic day 12.5, the erythropoietin receptor null mouse shows extensive apoptosis in fetal liver, heart and brain. Lack of erythropoietin receptor affects brain development as early as embryonic day 10.5. Neural progenitor cells exhibit a reduction in neuron generation and increased sensitivity to hypoxia. In contrast, erythropoietin stimulated proliferation of normal neural progenitor cells and provided a neuroprotective effect. Hypoxia induced erythropoietin receptor expression and increased erythropoietin sensitivity. Introduction of the human erythropoietin receptor in the erythropoietin receptor null mouse rescues in utero the severe anemia and defective cardiac and brain development. Induction of erythropoietin and its receptor by hypoxia support a therapeutic potential for erythropoietin administration for tissue damage from ischemia or hypoxic challenge. Neuronal cells appear to share common regulatory elements with hematopoietic cells in the expression of erythropoietin receptor. Hypoixia induction of the erythropoietin receptor and increase in erythropoietin responsiveness is also observed in endothelial cells. Long term erythropoietin administration for treatment of anemia associated with renal failure, has been associated with de novo hypertension, attributed in part to increased red cell mass and trapping of nitric oxide via direct binding to free hemoglobin. Immortalized human bone marrow endothelial cells, TrHBMEC, and human umbilical vein endothelial cells increased proliferation, endothelial nitric oxide synthase synthesis and nitric oxide production when exposed to hypoxia in combination with erythropoietin. Erythropoietin stimulation could not be attributed to induction of vascular endothelial growth factor or the vascular endothelial growth factor receptors, flt-1 or flk-1. These results suggest that in vivo, induction of erythropoietin by hypoxia can elicit an endothelial response with induction of EPOR, and that increased sensitivity to erythropoietin gives rise to increased endothelial nitric oxide synthase and nitric oxide production to counter the hypertensive effects of nitric oxide binding by increased hemoglobin mass. The multi-organ response to erythropoietin that includes hematopoietic, neuronal, endothelial and muscle cells underscores the similarities among respective differentiating somatic stem cells and suggests that erythropoeitin may be active in general tissue development, maintenance and/or stress response.